Globally circulating strains of HIV-1 are extraordinarily variable, and this diversity poses a major obstacle to AIDS vaccine development. Currently, all candidate vaccines are derived from contemporary HIV-1 isolates, often selected solely based on availability. It is hoped that these vaccines will be sufficiently cross-reactive to protect against other viruses circulating in the population. However, given that envelope diversity even within a subtype can be as high as 20%, this assumption may be overly optimistic. Reconstructed consensus or common ancestor sequences can be used to minimize the genetic differences between vaccine strains and contemporary isolates, effectively reducing the extent of diversity by half. In this project, we will test whether consensus immunogens elicit more broadly cross-reactive immune responses and thus represent better vaccines. Within this IPCAVD team effort, we will generate Virus-like Particle (VLP)-based and other HIV-1 and SIV consensus vaccines and compare their immunogenicity, in particular their ability to generate cross-reactive neutralizing antibody responses, with that of vaccines derived from single, contemporary HIV-1 and SIVmac isolates. We will also explore whether SIVcpz immunogens can be exploited for AIDS vaccine design. Specific aims include: 1. To synthesize HIV-1 subtype B consensus genes, incorporate these genes into first and second generation VLP-based vaccines, and conduct immunogenicity studies in mice and guinea pigs. We will determine whether synthetic consensus genes are functional and immunogenic in the context of VLP-based vaccine formulations, and whether they are superior to single strain derived vaccines in eliciting cross-reactive neutrafizing antibody responses. 2. To generate VLP, DNA and recombinant adenovirus based SIV consensus vaceines for a proof-of-principle study in a relevant animal model. We will test the consensus vaccine concept in non-human primates using a combination of different vaccines to induce strong and broadly cross-reactive humoral and T-cell responses. 3. To test whether SIVcpz derived envelope glycoproteins can be exploited as novel immunogens. We will explore the potential utility of SIVcpz based envelope immunogens for the induction of broadly cross-reacting neutralizing antibody responses. The overall goal of this project is to determine whether the theoretical advantages of consensus vaccines are born out experimentally in small animal models, non-human primates, and ultimately humans.